The present invention relates generally to ovarian cancer therapy. The invention is more specifically related to polypeptides comprising at least a portion of an ovarian carcinoma protein, and to polynucleotides encoding such polypeptides, as well as antibodies and immune system cells that specifically recognize such polypeptides. Such polypeptides, polynucleotides, antibodies and cells may be used in vaccines and pharmaceutical compositions for treatment of ovarian cancer.
Ovarian cancer is a significant health problem for women in the United States and throughout the world. Although advances have been made in detection and therapy of this cancer, no vaccine or other universally successful method for prevention or treatment is currently available. Management of the disease currently relies on a combination of early diagnosis and aggressive treatment, which may include one or more of a variety of treatments such as surgery, radiotherapy, chemotherapy and hormone therapy. The course of treatment for a particular cancer is often selected based on a variety of prognostic parameters, including an analysis of specific tumor markers. However, the use of established markers often leads to a result that is difficult to interpret, and high mortality continues to be observed in many cancer patients.
Immunotherapies have the potential to substantially improve cancer treatment and survival. Such therapies may involve the generation or enhancement of an immune response to an ovarian carcinoma antigen. However, to date, relatively few ovarian carcinoma antigens are known and the generation of an immune response against such antigens has not been shown to be therapeutically beneficial.
Accordingly, there is a need in the art for improved methods for identifying ovarian tumor antigens and for using such antigens in the therapy of ovarian cancer. The present invention fulfills these needs and further provides other related advantages.
Briefly stated, this invention provides compositions and methods for the therapy of cancer, such as ovarian cancer. In one aspect, the present invention provides polypeptides comprising an immunogenic portion of an ovarian carcinoma protein, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with ovarian carcinoma protein-specific antisera is not substantially diminished. Within certain embodiments, the ovarian carcinoma protein comprises a sequence that is encoded by a polynucleotide sequence selected from the group consisting of sequences recited in FIGS. 5, 8, 13, 16A-16I and 17A-17C (SEQ ID NOs:5, 8, 13, 19-68 and 69-85), SEQ ID NOs:130, 133, 135, 137, 138, 140, 142, 144-146, 148, 153, 155, 158, 159, 161, 163, 170, 174, 177, 178, 179, 180-182, 184, 187, 189, 190, 192, 195, 196, 198, 200, 207, 214-216, 220, 221, 222, 227, 228, 230, 231, 232, 234, 240-242, 243, 244-246, 250, 251, 253, 254, 256, 259, 261, 262, 264, 265, 272-275, 276, 278, 280, 281, 282, 283, 287, 288, 291, 292, 296, 297, 299, 301, 304-309, 311, 313, 314, 317, 323, 325 and 333, and complements of such polynucleotides.
The present invention further provides polynucleotides that encode a polypeptide as described above or a portion thereof, expression vectors comprising such polynucleotides and host cells transformed or transfected with such expression vectors.
Within other aspects, the present invention provides pharmaceutical compositions and vaccines. Pharmaceutical compositions may comprise a physiologically acceptable carrier in combination with one or more of: (i) a polypeptide comprising an immunogenic portion of an ovarian carcinoma protein, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with ovarian carcinoma protein-specific antisera is not substantially diminished, wherein the ovarian carcinoma protein comprises an amino acid sequence encoded by a polynucleotide that comprises a sequence recited in any one of FIGS. 5, 8, 13, 16A-16I and 17A-17C (SEQ ID NOs: 5, 8, 13, 19-68 and 69-85), SEQ ID NOs:130, 133, 135, 137, 138, 140, 142, 144-146, 148, 153, 155, 158, 159, 161, 163, 170, 174, 177, 178, 179, 180-182, 184, 187, 189, 190, 192, 195, 196, 198, 200, 207, 214-216, 220, 221, 222, 227, 228, 230, 231, 232, 234, 240-242, 243, 244-246, 250, 251, 253, 254, 256, 259, 261, 262, 264, 265, 272-275, 276, 278, 280, 281, 282, 283, 287, 288, 291, 292, 296, 297, 299, 301, 304-309, 311, 313, 314, 317, 323, 325 or 333, or a complement of any of the foregoing sequences; (ii) a polynucleotide encoding at least 5 amino acid residues of such an ovarian carcinoma protein; (iii) an antibody that specifically binds to such an ovarian carcinoma protein; (iv) an antigen-presenting cell that expresses a polypeptide as described above and/or (v) a T cell that specifically reacts with such a polypeptide. Vaccines may comprise a non-specific immune response enhancer in combination with one or more of: (i) a polypeptide comprising an immunogenic portion of an ovarian carcinoma protein, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with ovarian carcinoma protein-specific antisera is not substantially diminished, wherein the ovarian carcinoma protein comprises an amino acid sequence encoded by a polynucleotide that comprises a sequence recited in any one of FIGS. 5, 8, 13, 16A-16I and 17A-17C (SEQ ID NOs: 5, 8, 13, 19-68 and 69-85), SEQ ID NOs:130, 133, 135, 137, 138, 140, 142, 144-146, 148, 153, 155, 158, 159, 161, 163, 170, 174, 177, 178, 179, 180-182, 184, 187, 189, 190, 192, 195, 196, 198, 200, 207, 214-216, 220, 221, 222, 227, 228, 230, 231, 232, 234, 240-242, 243, 244-246, 250, 251, 253, 254, 256, 259, 261, 262, 264, 265, 272-275, 276, 278, 280, 281, 282, 283, 287, 288, 291, 292, 296, 297, 299, 301, 304-309, 311, 313, 314, 317, 323, 325 or 333, or a complement of any of the foregoing sequences; (ii) a polynucleotide encoding at least 5 amino acid residues of such an ovarian carcinoma protein; (iii) an anti-idiotypic antibody that is specifically bound by an antibody that specifically binds to such a polypeptide; (iv) an antigen-presenting cell that expresses such a polypeptide and/or (v) a T cell that specifically reacts with such a polypeptide.
The present invention further provides, in other aspects, fusion proteins that comprise at least one polypeptide as described above, as well as polynucleotides encoding such fusion proteins.
Within related aspects, pharmaceutical compositions comprising a fusion protein or polynucleotide encoding a fusion protein in combination with a physiologically acceptable carrier are provided.
Vaccines are further provided, within other aspects, comprising a fusion protein or polynucleotide encoding a fusion protein in combination with a non-specific immune response enhancer.
Within further aspects, the present invention provides methods for inhibiting the development of a cancer in a patient, comprising administering to a patient a pharmaceutical composition or vaccine as recited above.
The present invention further provides, within other aspects, methods for stimulating and/or expanding T cells, comprising contacting T cells with (a) a polypeptide comprising an immunogenic portion of an ovarian carcinoma protein, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with ovarian carcinoma protein-specific antisera is not substantially diminished, wherein the ovarian carcinoma protein comprises an amino acid sequence encoded by a polynucleotide that comprises a sequence recited in any one of SEQ ID NOs: 1-334; (b) a polynucleotide encoding such a polypeptide and/or (c) an antigen presenting cell that expresses such a polypeptide under conditions and for a time sufficient to permit the stimulation and/or expansion of T cells. Such polypeptide, polynucleotide and/or antigen presenting cell(s) may be present within a pharmaceutical composition or vaccine, for use in stimulating and/or expanding T cells in a mammal.
Within other aspects, the present invention provides methods for inhibiting the development of ovarian cancer in a patient, comprising administering to a patient T cells prepared as described above.
Within further aspects, the present invention provides methods for inhibiting the development of ovarian cancer in a patient, comprising the steps of: (a) incubating CD4+ and/or CD8+ T cells isolated from a patient with one or more of: (i) a polypeptide comprising an immunogenic portion of an ovarian carcinoma protein, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with ovarian carcinoma protein-specific antisera is not substantially diminished, wherein the ovarian carcinoma protein comprises an amino acid sequence encoded by a polynucleotide that comprises a sequence recited in any one of SEQ ID NOs:1-334; (ii) a polynucleotide encoding such a polypeptide; or (iii) an antigen-presenting cell that expresses such a polypeptide; such that T cells proliferate; and (b) administering to the patient an effective amount of the proliferated T cells, and thereby inhibiting the development of ovarian cancer in the patient. The proliferated cells may be cloned prior to administration to the patient.
These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.